Open Access
Review
EAACI position paper on occupational rhinitis
Gianna Moscato*
1, Olivier Vandenplas
2, Roy Gerth Van Wijk
3,
Jean-Luc Malo
4, Luca Perfetti
1, Santiago Quirce
5, Jolanta Walusiak
6,
Roberto Castano
4, Gianni Pala
1, Denyse Gautrin
4, Hans De Groot
3,
Ilenia Folletti
7, Mona Rita Yacoub
1and Andrea Siracusa
7Address: 1Allergy and Immunology Unit, Fondazione 'Salvatore Maugeri', Institute of Care and Research, Scientific Institute of Pavia, Pavia, Italy, 2Service de Pneumologie, Cliniques de Mont-Godinne, Université Catholique de Louvain, Yvoir, Belgium, 3Department of Allergology, Erasmus
MC, Rotterdam, The Netherlands, 4Center for Asthma in the Workplace, Hôpital du Sacré-Coeur de Montréal, Centre de Recherche-Pneumologie,
Montreal, Quebec, Canada, 5Allergy Department, Hospital La Paz, Madrid, Spain, 6Department of Occupational Diseases, Institute of
Occupational Medicine, Lodz, Poland and 7Occupational Medicine, Terni Hospital, University of Perugia, Perugia, Italy
Email: Gianna Moscato* - [email protected]; Olivier Vandenplas - [email protected]; Roy Gerth Van Wijk - [email protected]; Jean-Luc Malo - [email protected]; Luca Perfetti - [email protected];
Santiago Quirce - [email protected]; Jolanta Walusiak - [email protected]; Roberto Castano - [email protected]; Gianni Pala - [email protected]; Denyse Gautrin - [email protected]; Hans De Groot - [email protected]; Ilenia Folletti - [email protected]; Mona Rita Yacoub - [email protected]; Andrea Siracusa - [email protected] * Corresponding author
Abstract
The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.
Key messages
Definition and classification
• Occupational rhinitis is an inflammatory disease of the nose, which is characterized by intermittent or persistent symptoms (i.e., nasal congestion, sneezing, rhinorrea, itching), and/or variable nasal airflow limitation and/or hypersecretion due to causes and conditions attributable to a particular work environment and not to stimuli encountered outside the workplace
• Work-related rhinitis may be distinguished into: (1) occupational rhinitis that is due to causes and conditions attributable to a particular work environment (2) work-exacerbated rhinitis that is pre-existing or concurrent rhin-itis exacerbated by workplace exposures
Epidemiology
• Surveys of workforces exposed to sensitizing agents indi-cate that OR is 2 to 4 times more common than OA,
Published: 3 March 2009
Respiratory Research 2009, 10:16 doi:10.1186/1465-9921-10-16
Received: 5 November 2008 Accepted: 3 March 2009
This article is available from: http://respiratory-research.com/content/10/1/16
© 2009 Moscato et al; licensee BioMed Central Ltd.
although the contribution of workplace exposures to the general burden of rhinitis remains unknown
• The level of exposure is the most important determinant of IgE-mediated sensitization to occupational agents and OR
• Atopy is a risk factor for the development of IgE-medi-ated sensitization to HMW agents, but the association with clinical OR due to HMW agents is less well substan-tiated
Relationships with occupational asthma
• The majority of patients diagnosed with OA also suffers from OR, which most often precedes the development of OA, especially when HMW agents are involved
• OR is associated with an increased risk of asthma, although the proportion of subjects with OR who will develop OA remains uncertain
Investigation and diagnostic approach
• Questionnaires and the clinical history have a low spe-cificity for diagnosing OR
• Immunological tests (skin prick tests and specific IgE antibodies) are sensitive but not specific tools for diagnos-ing OR due to most HMW agents and some LMW agents (i.e., platinum salts, acid anhydrides, and reactive dyes)
• In the presence of work-related rhinitis symptoms, objective assessment using nasal provocation challenges in the laboratory or at the workplace should be strongly recommended
Management
• Complete avoidance of exposure to the agent causing allergic OR should still be recommended as the safest and most effective therapeutic option
• When complete elimination of causal exposure is expected to induce important adverse socio-economic consequences, reduction of exposure with relevant phar-macotherapy may be considered an alternative approach, especially in workers with a lower risk of developing asthma (e.g., workers without non-specific bronchial hyperresponsiveness, with mild/recent disease or with a short expected duration of exposure); these workers should however benefit from close medical surveillance aimed at an early detection of OA
Socio-economic impact
• The socio-economic impact of OR is unknown, but is likely to be substantial in terms of work productivity as
can be extrapolated from data available for allergic rhinitis in general
Prevention
• Primary prevention strategies should focus on reducing exposure to potentially sensitizing agents
• Identification and exclusion of susceptible workers is not efficient, particularly when the marker of susceptibil-ity (e.g. atopy) is prevalent in the general population
• Surveillance programmes aimed at an early identifica-tion of OR should include periodic administraidentifica-tion of questionnaires and immunological tests when available
• Surveillance of workers should focus on the first 2 to 5 years after entering exposure
• The possibility of OA should be carefully evaluated in all workers with OR
Medico-legal aspects
• Workers with OR should theoretically be considered impaired on a permanent basis for the job that caused the condition as well as for jobs with similar exposures
• Compensation of OR should aim at providing incen-tives to accommodate workers to unexposed jobs and offering vocational rehabilitation programs in order to minimize the adverse socio-economic consequences of the disease
Introduction
The health and socio-economic impact of rhinitis, as well as the interaction between upper and lower airways have been emphasized in recent years [1-8]. By contrast, little attention has been paid to occupational rhinitis (OR), although it is increasingly acknowledged that the burden of this condition is largely underestimated in comparison with occupational asthma (OA) [9-12] [see also Figure 1].
There is currently no consensus on the definition and clas-sification of OR. In addition, diagnostic procedures and strategies for the management of subjects with OR remain poorly standardized. This is a particularly important point as an accurate and early recognition of OR in surveillance programs is not only important per se, but is also useful in the prevention and early diagnosis of OA.
evi-dence and the expertise of a panel of physicians coming from different European and non European countries.
Definition and classification
The most widely cited definition of rhinitis has been for-mulated by the International Consensus Report and states that 'rhinitis is defined as inflammation of the lining of the nose, characterized by one or more of the following symptoms: nasal congestion, rhinorrhea, sneezing, and itching' [1,13]. This International Consensus Report has proposed an operational definition of rhinitis which was based solely on symptoms and would require the presence of 'two or more nasal symptoms for more than one hour on most days', although these criteria have never been formally validated [14-16].
Most previously published definitions of OR were based
on the temporal relationship between nasal symptoms
and workplace exposure [13,17-20], while a few others also refer to the underlying inflammation [12,21]. How-ever, the major symptoms of OR (i.e., sneezing, rhinor-rhea, nasal congestion, and itching) are similar to those of non-occupational rhinitis. Defining OR based only on work-related symptoms would therefore suffer the limita-tion of being inaccurate [22], as already outlined for OA [23].
In addition, the similarities and tight interactions between rhinitis and asthma [1-8] support the need for homogene-ous definitions of OR and OA. The most widely accepted definition of OA refers to the pathophysiological changes that occur in the lower airways, i.e. 'variable airflow limita-tion and/or bronchial hyperresponsiveness and/or
inflamma-tion' [24,25]. A similar approach cannot easily be
translated to OR because: (1) nasal airflow limitation is not always present in OR; and (2) the various methods
Parallel classification of occupational rhinitis and asthma
Figure 1
Parallel classification of occupational rhinitis and asthma. The Table classifies occupational rhinitis according to the most recent classification of occupational asthma. RADS, Reactive Airways Dysfunction Syndrome; RUDS, Reactive Upper Air-ways Dysfunction Syndrome).
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used for assessing nasal patency, non-specific hyperre-sponsiveness, and inflammation have not been thor-oughly validated [26,27], and (3) these procedures are still largely underused in clinical practice. Nevertheless, considering that inflammatory changes of the mucosa are the common feature of both rhinitis and asthma [1-8,12], the following consensus definition of OR is proposed:
'Occupational rhinitis is an inflammatory disease of the nose, which is characterized by intermittent or persistent symptoms (i.e., nasal congestion, sneezing, rhinorrea, itch-ing), and/or variable nasal airflow limitation and/or hyper-secretion due to causes and conditions attributable to a particular work environment and not to stimuli encoun-tered outside the workplace'.
The central concept of this broad definition is the causal relationship between work exposure and the development of the disease. In addition, this definition is based on demonstrable pathophysiological changes, and it does not place restriction according to the underlying mecha-nism.
There is accumulating evidence that the workplace envi-ronment can induce or trigger a wide spectrum of rhinitis conditions involving immunological and non-immuno-logical mechanisms [16,20,28,29]. These various condi-tions should be referred to as 'work-related rhinitis' and should be further distinguished according to the clinical features, etiopathogenic mechanisms, and the strength of the evidence supporting the causal relationship.
According to the revised nomenclature for allergy recently recommended by the European Academy of Allergy and Clinical Immunology [30] and the classification of work-related asthma proposed by panels of experts [24,25,31] different types of 'work-related rhinitis' may be delineated as detailed below and summarized in Figure 1. This review will, however, focus on immunologically-mediated OR, since there is only scarce data on the other forms of work-related rhinitis.
Occupational rhinitis
Allergic OR
Work-related rhinitis symptoms are caused by immuno-logically-mediated hypersensitivity reactions resulting from antibody- or cell-mediated mechanisms. This entity is characterized clinically by the development of nasal hypersensitivity to a specific occupational agent appearing after a latency period, which is necessary to acquire immu-nological sensitization to the causal agent. Once initiated, the symptoms recur on re-exposure to the sensitizing agent at concentrations not affecting other similarly exposed workers. The symptoms can be intermittent or persistent according to the frequency and intensity of
exposure to the causal agent. In allergic OR, the causal role of occupational agents can be documented on an individ-ual basis through nasal provocation test (NPT), showing reduction of nasal patency, increased volume of nasal secretions, and/or nasal inflammation. Allergic OR encompasses both IgE-mediated OR and non-IgE-medi-ated OR.
1. IgE-mediated OR: Can be caused by a wide variety of
high-molecular weight (HMW) agents (i.e. glycoproteins from vegetal and animal origin) and some low-molecular-weight-agents (LMW) for which an IgE-mediated mecha-nism has been proven, such as platinum salts, reactive dyes, and acid anhydrides.
2. Non-IgE-mediated OR: Can be induced by LMW agents
(e.g. isocyanates, persulphate salts, woods) acting as hap-tens for which the allergic mechanism has not yet been fully characterized.
Non-allergic OR
This category encompasses different types of rhinitis caused by the work environment through irritant, non-immunological mechanisms. It has been documented that single or multiple exposures to very high concentra-tions of irritant compounds can lead to transient or per-sistent symptoms of rhinitis [32-34]. Such cases of acute-onset 'irritant-induced OR' usually occur without a latency period, although the absence of latency may be obscured when workers are repeatedly exposed to high levels of irri-tants at work. This entity is quite similar to the situation
of 'reactive airways dysfunction syndrome' (RADS)
[25,31,35], so that the term 'reactive upper airways dysfunc-tion syndrome' (RUDS) has been proposed [36]. Biopsies of the nasal mucosa among individuals with RUDS induced by chlorine have shown non specific pathologic changes (i.e., lymphocytic inflammation of the lamina propria, epithelial desquamation, defective epithelial cell junc-tions, and increased numbers of nerve fibres) [32]. In these cases of irritant-induced OR, evidence supporting a causal relationship with the workplace can be drawn only from the temporal association between exposure to unu-sually high levels of irritants and the development of rhin-itis symptoms (or other objective indices of the disease).
of polyurethanes, and waste handling [12,21]. The symp-toms may be experienced only during exposure to irritants at work or may be persistent, presenting both at work and off work.
The term 'corrosive rhinitis' has been used to describe the most severe form of 'irritant-induced OR', which is char-acterized by permanent inflammation of the nasal mucosa (sometimes associated with ulcerations and per-foration of the nasal septum) that may develops after exposure to high concentrations of irritating and soluble chemicals [20,29,37].
Work-exacerbated rhinitis
Work-exacerbated rhinitis (WER) should be defined as pre-existing or concurrent (allergic or non-allergic) rhini-tis that is worsened by workplace exposures [22,29], while the disease has not been caused by the work environment. It is indeed highly likely that rhinitis symptoms can be triggered by a wide variety of conditions at work, includ-ing irritant agents (e.g., chemicals, dusts, fumes), physical factors (e.g., temperature changes), emotions, second-hand smoke, and strong smells (e.g., perfumes). Epidemi-ological surveys have usually found high prevalence rates of work-related nasal symptoms in a variety of workforces, although IgE-mediated sensitization to occupational agents was not detected [22,38-42]) or nasal inflamma-tion was not documented [43-47].
The clinical features of a WER are similar to those of occu-pational rhinitis, so that the possibility of a WER should be considered only after careful exclusion of a specific sen-sitization to a workplace agent through appropriate diag-nostic procedures. The mechanisms involved in the development of WER have been scarcely explored. The nasal response to irritant stimuli show wide inter-individ-ual variability, and exaggerated reactivity to common chemical and physical stimuli, and is affected by age, gen-der, and the presence of allergic rhinitis [48-50].
Epidemiology
Prevalence and incidence
Although rhinitis is a common condition, the prevalence and incidence of OR in the general population have almost never been specifically investigated. Analysis of incident cases of OR reported to the Finnish Register of Occupational Diseases during the period 1986–1991 showed that occupations at increased risk include furriers, bakers, livestock breeders, food-processing workers, veter-inarians, farmers, electronic/electrical products assem-blers, and boat builders [51].
Cross-sectional studies have been conducted in various working populations exposed to a wide range of HMW and LMW agents, as recently reviewed [9]. Prevalence rates
of OR varied from 2% to 87% in workforces exposed to HMW agents and from 3% to 48% in those exposed to LMW agents (Table 1). Available data indicate that OR is usually 2–4 times more prevalent than OA [9,52]. Preva-lence estimates of rhinitis and OR are largely affected by the criteria used for identifying the condition [52]. The incidence of work-related nose symptoms (WRNS) has been investigated in a few prospective cohort studies that are summarized in Table 2[38-41,53,54].
Risk factors
Exposure, atopy, and smoking have consistently emerged as the main potential determinants for the development of OR.
Level of exposure
A dose-response gradient between the level of exposure and IgE-mediated sensitization has been substantiated for various HMW agents, such as laboratory animals [55,56], flour [57,58], insects [59], alpha-amylase [60], and deter-gent enzymes [61]. However, much of the evidence relates more strongly to immunological sensitization (i.e., the development of specific IgE antibodies) than to clinical OR [9]. Although the relationships between these two outcomes are poorly understood, the development of IgE sensitization to some agents seems to be a strong predic-tor of rhinitis/asthma symptoms [41,62-64].
Atopy
Atopy has been associated with an increased risk of spe-cific sensitization to a variety of HMW agents [9,52]. Atopy is associated with OR due to these agents (Table 1) [41,65,66]. Available studies have provided inconsistent results regarding the relationships between atopy and OR or specific sensitization in workers exposed to LMW agents [9,63] but atopy is unlikely to play a role.
Unlike occupational asthma, the role of genetic factors in the development of OR has never been specifically assessed. [67].
Smoking
The relationships between smoking and occupational sen-sitization, OR, and OA remain controversial [68-70].
Non-specific bronchial hyperresponsiveness
There is some evidence from cohort studies [63,71] that non-specific bronchial hyperresponsiveness may be asso-ciated with an increased risk for the subsequent develop-ment of work-related nasal symptoms.
Relationships with occupational asthma
respi-Table 1: Prevalence and aetiological agents in occupational rhinitis (adapted from reference [9]).
Agents Occupation Prevalence (%)
High molecular weight agents
Laboratory animals Laboratory workers 6–33
Other animal-derived allergens Swine confinement workers 8–23
Insects & mites Laboratory workers, farm workers 2–60
Grain dust Grain elevators 28–64
Flour Bakers 18–29
Latex Hospital workers, textile factory 9–20
Other plant allergens Tobacco, carpet, hot pepper, tea, coffee, cocoa, dried fruit and saffron workers 5–36
Biological enzymes Pharmaceutical & detergent industries 3–87
Fish and seafood protein Trout, prawn, shrimp, crab & clam workers; aquarists & fish-food factory workers 5–24
Low molecular weight agents
Diisocyanates Painters, urethane mould workers 36–42
Anhydrides Epoxy resin production, chemical workers, electric condenser workers 10–48
Wood dust Carpentry & furniture making 10–36
Metals (platinum) Platinum refinery 43
Drugs (psyllium, spiramycin, piperacillin) Health care & pharmaceutical workers 9–41
Chemicals Reactive dye, synthetic fibre, cotton, persulphate, hairdressing, pulp & paper, shoe manufacturing
3–30
Table 2: Incidence of occupational asthma and rhinitis
Reference/agent Subjects N
Years/duration (yrs) of follow-up
Incidence of OA* (× 100 person years)
Incidence of OR** (× 100 person years)
Cullinan el al., 1999/laboratory animals [38] 342 1990–1993/2.7 3.5 7.3
Rodier et al., 2003/laboratory animals [39] 387 1993–1995/3.7 2.7 12.1
Draper et al., 2003/laboratory animals [54] 17300 1999–2000/1.0 0.2 0.3
Cullinan et al., 2001/flour [40] 1990–1993/3.3 4.1 11.8
Gautrin et al., 2002/flour [41] 1993–1997/1.4 NA*** 13.1
Archambault et al., 2001/latex [53] 1993–1995/2.7 1.8 0.7
ratory system [2,5,7]. The 'united airway disease' model describes such a relationship as two clinical manifesta-tions of a single disorder. The evidence of this relamanifesta-tionship comes from the observation of common epidemiologic [72], physiopathologic, [73], clinical and therapeutic fea-tures in both conditions [2,3]. These links have been more frequently observed when considering allergic mecha-nisms, but the concept of a unique disease has evolved and non-allergic mechanisms may be considered as well.
With regard to the association between rhinitis and asthma of occupational origin, Malo and coworkers have documented that rhinitis symptoms are common among subjects with OA, 92% patients with OA reporting symp-toms of OR [74]. The prevalence of rhinitis sympsymp-toms was not different for HMW and LMW agents, although the intensity of symptoms was more pronounced for HMW agents. A recent prospective study carried out in patients referred to four tertiary care clinics for possible OA, showed that nasal itching and secretions as well as ocular itching were satisfactory predictors of the presence of OA as confirmed by specific inhalation challenges [75]. How-ever, this likely prediction obtained from questionnaire items applied for HMW but not for LMW agents.
Symptoms of OR have been reported to develop before those of OA in 20 to 78% of affected subjects [22,64,74,76-80]. There is some suggestion that symp-toms of OR were more often reported to precede OA in the case of HMW compared to LMW agents [74,77]. A lon-gitudinal study of patients seeking compensation for OR from the Finnish Register of Occupational Diseases, fol-lowed via register linkage showed an increased risk of asthma (RR 4.8, 95%CI 4.3 to 5.4) among those with OR compared to subjects with other occupational diseases [81]. The incidence rate ratio for asthma in workers with occupational rhinitis varied across occupations, being highest for farmers and woodworkers [81].
The time-course pertaining to the development of immu-nological sensitization and nasal or respiratory symptoms related to the onset of exposure has seldom been exam-ined. As for environmental allergens, it can be hypothe-sized that workers first develop immunological reactivity and subsequent to this, symptoms related to a specific organ (skin, nasoconjunctival, respiratory), this sequence being referred to as the 'allergic march'. Among appren-tices in animal health technology [62], development of skin reactivity and nasoconjunctival symptoms mainly occurred in the first two years after starting exposure, con-firming the findings of a longitudinal study of animal workers [38], whereas onset of respiratory symptoms was more common in the second and third year of the appren-ticeship program. In this study, the predictive value of the development of work-related nasal symptoms on the
sub-sequent development of probable OA was only 11.4% over a 44-months period [62]. An annual surveillance program of workers exposed to laboratory animals (582 workers contributing 2414 person-years) found that the probability of experiencing asthma symptoms by the 11th year of follow-up was 36.7% for workers with animal-related rhinoconjunctivitis symptoms and 5.2% for those without allergy symptoms [82]. By contrast, a 24-month prospective study of apprentice bakers showed that OR could be diagnosed at an earlier stage in only 20% of cases of OA [64].
Investigation and diagnostic approach
The investigation of OR includes both assessing the pres-ence of rhinitis and demonstrating their work-relatedness. The use of objective methods to assess nasal patency and parameters of inflammation in nasal secretions mini-mizes patient misclassification.
The diagnosis needs to be confirmed by means of objec-tive methods, as misdiagnosis may have substantial social and financial consequences. The different steps involved in the diagnosis of OR are the clinical history, nasal exam-ination, immunological tests (for allergic OR), and nasal provocation tests (NPT) [see Figure 2].
In addition, the possibility of lower airways involvement should be carefully evaluated by means of questionnaire, spirometry, measurement of non-specific airway respon-siveness [1,83,84] and evaluation of inflammation by means of exhaled NO [85].
Clinical and occupational history
Detailed medical and occupational history remains a key step in investigation and diagnosis of OR. The occupa-tional history should aim at collecting a thorough descrip-tion of current worker's job duties, processes in adjacent work areas, recent changes in work processes or materials, and workplace hygiene conditions. Safety data sheets of the compounds to which the subject is directly and indi-rectly exposed should be gathered.
One purpose of the medical history when evaluating OR is to establish the timing of nasal symptoms in relation with occupational exposure, as suggested for OA [75,86]. History taking should address the following features: duration of employment at current job before onset of symptoms (latency period); agents, tasks or processes associated with the onset or aggravation of symptoms; improvement away from work (weekends or prolonged holidays).
sim-ilar to those experienced by individuals from the general population with non-occupational rhinitis (i.e. rhinor-rhea, sneezing, nasal blockage, and itchy nose). Conjunc-tival complaints often accompany these symptoms, especially in allergic IgE-mediated OR. [74] A prospective study carried out among a large cohort of animal-health apprentices showed that symptoms such as sneezing, rhi-norrhea and itchy eyes (typical of an early temporal reac-tion after exposure to an allergen) tended to develop early after starting exposure, whereas symptoms such as stuffy nose appeared later [39].
Although an essential step of the diagnostic approach, the clinical history is not specific enough to establish a diag-nosis of allergic OR [22,38-41,52].
Nasal examination
Unlike the lower airways, the nose provides a unique opportunity to visualize macroscopic appearance of the nasal mucosa using anterior rhinoscopy and nasal endos-copy. These techniques, however, do not allow quantita-tive assessment of nasal changes. Their main value is to rule out other nasal pathologies that may mimic rhinitis or contribute to aggravate nasal obstruction (e.g, septal deviations, nasal polyps) in patients with rhinitis.
Physiological assessment
Nasal patency
Objective methods that can be used for assessing nasal patency during the investigation of OR include rhinoma-nometry, acoustic rhinometry and peak nasal inspiratory
Diagnostic algorithm
Figure 2
Diagnostic algorithm. The figure illustrates the sequential steps for diagnosing occupational rhinitis.
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flow (PNIF) [26,87,88]. These techniques share a com-mon great inter-individual variability that limits their applicability in clinical practice. Thus, it is not possible to rely on comparisons with reported values of healthy sub-jects to make a diagnosis of rhinitis. Nevertheless, the above methods have well-defined reproducibility, whereby their use is justified for evaluating nasal response to NPTs, during which patients act as their own control.
Anterior rhinomanometry measures separately the airway resistance of each nostril. The technique requires relatively little patient instruction and is easy to perform, but meas-urements are difficult when the nostril becomes occluded. Posterior rhinomanometry assesses the total resistance of nasal airways through an oral catheter in the pharynx, but the technique requires collaboration of the patients [89]. Available studies provide conflicting data regarding the correlation of rhinomanometry with nasal symptoms. The measurement of peak nasal inspiratory flow (PNIF) has been proposed as a simple, inexpensive, and readily available tool for evaluating nasal airway patency [90]. A good correlation between PNIF and rhinomanometry has been shown by some reports [91-93], but PNIF is less sen-sitive in detecting changes in nasal patency [94]. Serial self-measurements of peak nasal inspiratory flow can be performed to assess airflow obstruction at the workplace. Acoustic rhinometry is a relatively new technique that assesses nasal patency by determining the cross-sectional area and volume of nasal cavities using the reflection of sound waves [89]. This technique is non-invasive, repro-ducible, and requires little cooperation from the patient [95]. This technique has been useful for demonstrating cross-shift changes in nasal patency in different industries and would be promising for workplace challenges.
Nasal inflammation
Inflammatory cells and mediators can be measured in nasal secretions [27]. Nasal secretions can be collected and weighted for quantifying the secretory activity, espe-cially after allergen challenges [96,97]. The use of nasal lavage in clinical practice is still limited due to great inter-individual variability and the lack of a standardized and validated method. Accordingly, this technique is more useful in situations where subjects serve as their own con-trols as it occurs during NPT or exposure at the workplace. Inflammatory cells can also be assessed using nasal biop-sies [27], whose applicability is limited by their invasive character, or using nasal scrapings or brush samples, which are simple and relatively painless procedures [98]. In subjects with allergic rhinitis, a good correlation has been found between nasal eosinophils and clinical parameters, including nasal symptoms and nasal patency [99]. More recently, measurement of nasal nitric oxide (NO) has been proposed as a non-invasive marker of nasal inflammation [85,100]. There are currently no data
pertaining to the usefulness of measuring nasal NO in the investigation of OR.
Non-specific nasal hyperreactivity
Non-specific nasal hyper-reactivity is an important feature of allergic and non-allergic rhinitis and can be defined as an increased nasal response to a normal stimulus resulting in sneezing, nasal congestion, and/or nasal secretion [101,102]. By contrast to bronchial hyperreactivity in asthma, nasal hyperreactivity is not so much documented in occupational rhinitis. Nasal challenge tests with hista-mine, methacholine [102-104] and cold dry air [105,106] have been proposed as a method to quantify non-specific upper airway hyperreactivity. Histamine and metha-choline responsiveness represent different forms of upper airway hyperreactivity [101,102]. Histamine is by far the most commonly used stimulus and hyperreactivity to his-tamine has been convincingly demonstrated to occur after allergen provocation [107,108]. Methacholine hyperreac-tivity has been reported to increase after allergen provoca-tion [109] but not all studies reproduced these findings [110]. Intranasal cold dry air has been shown to be supe-rior to histamine challenge in measuring nasal hyperreac-tivity in nonallergic non infectious perennial rhinitis [105,106].
Immunological tests
The demonstration of IgE-mediated sensitization to occu-pational agents can be achieved by means of skin prick test and/or assessment of serum allergen-specific IgE anti-bodies. However, the sensitivity and specificity of immu-nological tests have almost never been established in comparison with NPTs. In recent studies, only 42% of subjects with work-related rhinitis and positive skin-prick tests to laboratory animals showed a positive NPT with relevant allergen extracts [52]. Among 47 bakery appren-tices who developed work-related rhinitis symptoms over a 2-year period, NPT was positive in the 36 subjects dem-onstrating IgE sensitization to flour but also in two sub-jects with negative immunological tests [64]. Positive immunological test may occur in a substantial proportion of exposed asymptomatic individuals [63,111-114], so that the specificity of immunological tests may be lower than their sensitivity. On the other hand, a negative test result makes the diagnosis of OR unlikely, provided that the appropriate allergens have been tested. The major lim-itation of immunological tests in the investigation of occupational allergy results from the lack of commercially available and standardized extracts for most occupational agents, especially LMW agents.
Nasal provocation tests
direct observational approach, the causal relationship between exposure to a specific occupational agent and elicitation of the characteristic features of rhinitis. NPTs can be performed either in the laboratory under control-led conditions or at work under natural conditions. The methods that can be used to deliver occupational agents and to measure nasal response during NPTs have been critically reviewed [9,26,27,88,97,115-120] and recom-mendations have been published by the European Acad-emy of Allergy and Clinical Immunology [119] and the Committee on Objective Assessment of the Nasal Airways of the International Rhinologic Society [88]. The method-ology of NPTs is described in detail in Appendix 1. The major limitation of these tests results from the fact that various criteria have been used for defining a positive response [115-118,120-123], but there is a lack of vali-dated comparison between these criteria [96].
Diagnostic algorithm
Exploring the work-relatedness of rhinitis symptoms remains often difficult, since diagnostic procedures should be adapted to various agents, occupational set-tings, and available resources. A consensus diagnostic algorithm has been elaborated (Figure 2) by taking into account the following practical constraints: (1) the valid-ity of the tests used for diagnosing OR remains largely uncertain and (2) the level of reliability may vary accord-ing to the purpose of the diagnostic evaluation and its expected socio-economic impact.
The first step includes a thorough clinical and medical his-tory, as well as nasal examination. If the suspect of an occupational origin is raised the work-relatedness of the rhinitis should be confirmed by objective methods. The second step includes the evaluation of sensitization to suspected occupational agents through immunological tests (skin-prick tests and/or determination of specific IgE antibodies) for most HMW agents and some LMW agents (i.e. platinum salts, reactive dyes, and acid anhydrides) [124]. A suggestive clinical history plus a positive immu-nological tests for a well-standardized extract could be considered as probable OR.
The next step involves the objective evaluation of the causal relationship between rhinitis and the work envi-ronment through NPTs in the laboratory. If NPT is posi-tive, a definite diagnosis of OR can be established. If NPT is negative, in the presence of a highly suggestive clinical history further evaluations of work-related changes in nasal symptoms, in nasal patency and in nasal inflamma-tion at the workplace or after a period at work are recom-mended. Assessment at the workplace may be first considered when NPT in the laboratory is not feasible (See Appendix 1).
Management
The management of OR has a two-sided objective: (1) minimizing nasal symptoms and their impact on the patients' well-being and (2) preventing the development of OA. Therapeutic options include environmental inter-ventions aimed at avoiding exposure to the causal agent and pharmacologic treatment [21]. Due to the tight rela-tionships between OR and OA a closer collaboration between different specialists, ENT, pneumologists and physicians with expertise in occupational medicine and in environmental hygiene may be recommended.
Environmental interventions
Treatment strategies should focus on avoidance of expo-sure to the agent causing allergic OR. However, complete avoidance of exposure often implies considerable profes-sional changes for affected workers and is associated with substantial socio-economic consequences [125,126]. Reduction of exposure can be achieved through different ways. Helmet respirators have been shown to be partially effective in reducing the consequences of exposure in patients with OR and asthma due to laboratory animals [127] and to latex [128]. However, the use of these protec-tive respiratory equipments should be considered only for protecting from peak exposures.
Removal from exposure
Available data indicate that rhinitis could be an early marker of OA. However, having few quantitative esti-mates [62,81,82] of the long-term risk of asthma among patients with OR makes it difficult to decide whether a worker suffering from this condition should be immedi-ately and completely removed from causal exposure. Therefore, advising a worker with OR to avoid exposure should take into account the following elements.
1. Additional risk factors for the development of asthma
There have been few attempts to determine which patients with allergic rhinitis have the highest risk of developing asthma. A study of patients suffering from allergic rhinitis found that those with non-specific bronchial hyperre-sponsiveness have a higher risk of asthma [129]. Popula-tion studies have confirmed that asymptomatic airway hyperresponsiveness is associated with a more frequent onset of asthma [130-132]. It has been also demonstrated that tboth the severity and duration of allergic and non-allergic rhinitis were important cofactors in determining the risk of developing asthma [133].
2. Possibilities for minimizing adverse socio-economic consequences
3. Possibilities for reducing exposure
In workplaces where the level of exposure can be signifi-cantly reduced, maintaining workers at their job may be considered a reasonable alternative [135], provided that workers with OR are submitted to close medical surveil-lance.
The outcome of OR after environmental interventions or removal from exposure has been seldom specifically investigated. In the few follow-up studies of OA that have evaluated concomitant OR, it has been found that the severity of rhinitis improved substantially after reduction of exposure to platinum salts [136] and latex [135,137]. Nevertheless, there is some suggestion that nasal symp-toms do not completely resolve even after complete avoidance [135], although it remains unknown whether allergic OR can lead to persistent functional sequelae. In non occupational setting, allergic rhinitis is not associated with remodelling of the nasal mucosa to the same extent as what has been described in asthmatic airways [138,139]
Pharmacotherapy and immunotherapy
No studies have addressed pharmacotherapy in OR, either allergic or allergic. Nevertheless, analogous to non-occupational allergic rhinitis (AR) it may be suggested that it should be instituted according to evidence-based guidelines, such as those proposed by the Allergic Rhinitis and its Impact on Asthma (ARIA) panel of experts http:// www.whiar.com[1]. The effect of non-sedating antihista-mines and intranasal corticosteroids medications has almost never been specifically assessed in alleviating work-related symptoms of rhinitis. However, in allergic OR, medications should not be considered a suitable alternative to elimination or reduction of workplace expo-sure to the sensitising agent.
Several studies have reported some improvement in respi-ratory symptoms during immunotherapy with purified rodent proteins, wheat flour extracts, and natural rubber latex. However, allergen immunotherapy is currently lim-ited by the unavailability of standardized extracts for most occupational allergens and should be used with caution and close supervision until more data are available [140].
Socio-economic impact
The socio-economic impact of OR has almost never been specifically evaluated and available data thus relate to other forms of rhinitis. Direct costs attributed to allergic rhinitis seem to be rather modest [141-144]. There is, however, growing evidence that important components of the economic burden of allergic rhinitis are indirect cost resulting from the worsening of associated airway diseases (sinusitis, asthma) [145-147], adverse effects of pharma-cological treatment [148-152], disease-related loss of
work productivity [151,153,154]. The impact of OR on work productivity has been evaluated in a retrospective cohort study of Swedish bakers [155]. Bakers reported having changed their job because of nasal symptoms more often than control subjects. In a study of Norwegian bakeries, the authors mentioned that, during a 2-year fol-low-up, 5 of 180 workers had to 'leave their jobs due work-related rhinitis, conjunctivitis and/or skin problems but none as a result of asthma' [22].
There is little information on the psycho-social impact of OR, although it has been increasingly recognized that allergic diseases may impair patients' quality of life [153,156-158]. The negative impact of OR on daily life has been investigated in only one study conducted among greenhouse workers [159].
Prevention
Primary prevention actions focus on environmental and host risk factors in order to prevent the development of OR. Secondary prevention aims to detect OR at an early stage and to take appropriate actions to minimize its dura-tion and severity. Tertiary prevendura-tion is applicable only to patients with established OR (see section on Manage-ment). Since OR is acknowledged as a risk factor for the development of OA, the prevention of work-related rhin-itis may also provide an excellent opportunity to prevent OA.
Primary prevention
Epidemiological data indicate that the level of exposure to sensitizing agents is the most important determinant of IgE-mediated sensitization and OR and, by implication, reducing or eliminating workplace exposure to sensitising agents should be the most effective approach for minimiz-ing the incidence of the disease.
Controlling exposure at the workplace
Examples of effective prevention resulting from reduction of exposure have been documented in enzyme detergent production [160-162], platinum refining workers [163], laboratory workers [164-166], and health care workers using latex gloves [167-171]. One study found a low rate of sensitization to diphenylmethane diisocyanate in a ure-thane mold plant that had been designed to minimize MDI exposure [86].
0.5 mg/m3 for flour dust [60,112,174], 0.25 ng/m3 for fungal α-amylase allergens [60], 0.7 μg/m3 for urinary rat allergens [175], and 0.6 ng/m3 for natural rubber latex allergens [176]. However, methods for measuring air-borne levels of biological agents are not fully standardized and are not yet easily available for evaluating the efficacy of environmental interventions [177].
Identification of susceptible workers
The positive predictive values of available susceptibility markers are too low for screening out potentially suscep-tible individuals [178,179]. This is particularly true in the case of atopy, which is a highly prevalent trait in the gen-eral population. Excluding atopic individuals from jobs entailing exposure to HMW allergens would reduce dra-matically the number of potential new employees and would be unduly discriminatory. In addition, there is a role for better education on the risk of sensitization of those attending vocational schools [178].
Secondary prevention
The short latency period for the incidence of OR indicates the need for surveillance of individuals at risk in the very first years of exposure [180]. Surveillance programs should be implemented during vocational training, since sensitization to occupational allergens and work-related nasal symptoms can develop at that time [39,41,53, 71,181-184].
Medical surveillance programmes should include the fol-lowing components [178,185,186]: (1) pre-placement and periodic administration of a questionnaire aimed at detecting work-related symptoms; (2) detection of sensiti-zation to occupational agents by means of skin prick tests or serum specific IgE antibodies when these tests are avail-able and standardized; (3) early referral of symptomatic and/or sensitized workers for specialized medical assess-ment, including NPT in the laboratory and/or at the work-place [52]; and (4) investigation of possible asthma in all workers with confirmed OR. Unfortunately, the effective-ness of secondary prevention has been studied in few set-tings and it is often difficult to distinguish the beneficial effects attributable to medical surveillance from those arising as a result of concurrent interventions [162]. In addition, the predictive value of immunological tests for the development of OR and OA may be high for some agents (e.g. platinum salts or acid anhydrides) [187,188], but much lower for other occupations [62].
Medico-legal aspects
Assessment of impairment/disability
Considering that persistence of exposure to agent causing allergic OR, will lead to worsening of the disease and is associated with a risk of asthma, patients with ascertained OR should, theoretically, be considered impaired on a permanent basis for the job that caused the condition as
well as for jobs with similar exposures. Evaluating the level of functional impairment due to OR is hampered by the absence of reference values for physiological tests. Impairment may take into account the fact that OR may be associated with the development of nasal responsive-ness to a variety of physical and chemical stimuli [48,49,101,189] and co-morbid conditions, including olfactory dysfunction, sinusitis, and sleep disorders [190-192]. Assessment of disability should be based on the severity of symptoms and their impact on global health status and quality of life. Quality of life can be assessed using validated instruments [156-158,193-196], although these questionnaires are not currently applicable for use as a clinical tool in individual patients. A classification of rhinitis severity into "mild" and "moderate/severe" has been proposed by the Allergic Rhinitis and its Impact on Asthma (ARIA) based on the impact of symptoms on sleep and daily life [1]. Rhinitis should be considered "moderate/severe" when symptoms are troublesome or when they are associated with sleep disturbance or impairment in daily activities, including work, school, lei-sure and sport. Visual analogue scales (VAS) have also been recommended by the European Consensus on Rhi-nosinusitis and Nasal Polyps [197] and the American Taskforce on Practice Parameters [198] for quantifying rhinitis and rhinosinusistis symptoms. According to the latest European Position Paper on Rhinosinusitis and Nasal Polyps 2007 the severity of rhinitis can be divided into mild, moderate and severe based on total severity vis-ual analogue scale (VAS) score (0–10 cm): mild (VAS 0– 3), moderate (VAS >3–7), severe (VAS >7–10) [199]. The simple ARIA grading system of rhinitis severity have been shown to correlate with impairment in quality of life, quality of sleep, and work productivity [192,200], VAS score [201], and health care utilization [202].
Compensation
countries' regulations, compensation may cover different aspects: physiological impairment, work disability, loss of income, health care costs, and professional retraining. Available data for OA indicate that the economic conse-quences of allergic occupational diseases are determined mainly by socio-demographic factors, while the severity of the condition has only a minimal effect [126]. Accord-ingly, it is not surprising that compensation based on physiological impairment does not adequately offset the financial consequences of the disease [126]. There is now a growing consensus that compensation systems should be directed at accommodating workers to unexposed jobs within the same company and to offer structured rehabil-itation programmes when required [179]. Affected work-ers should also benefit from adequate wage replacement during the period of professional retraining.
Unmet needs and research areas
Definition and classification
• Characterization of the clinical features and pathophys-iological mechanisms of 'non-allergic OR' and 'work-exac-erbated rhinitis'
Epidemiology
• Quantification of the contribution of OR to the general burden of rhinitis in the general population
• Development and validation of an international ques-tionnaire to identify OR in epidemiological surveys and clinical practice
• Further characterization of the role of atopy and smok-ing in the development of OR
• Elucidation of the interaction between upper and lower airway responses to sensitizing and irritant agents in the workplace
Diagnosis
• Standardization of occupational allergen extracts for skin prick tests and for assessment of serum specific IgE
• Standardization and validation of techniques used for measuring non-specific nasal hyperreactivity, nasal air-flow, and nasal inflammation
• Development and standardization of nasal provocation tests, including standardization of end points, evaluation of the role of nasal NO measurement, and identification of the most useful biological markers of nasal response
Management
• Specific assessment of the impact of OR in terms of QoL and economic burden in order to evaluate the cost-effec-tiveness of therapeutic and preventive interventions
• Prospective assessment of the efficacy and safety of immunotherapy with occupational agents in controlling rhinitis symptoms and preventing the development of OA
Prevention
• Identification of parameters influencing the prognosis of OR
• Assessment of the effects of environmental interventions on the clinical and physiological indices of rhinitis, such as the level of non-specific nasal hyperresponsiveness, and nasal inflammation
• Assessment of the impact of environmental interven-tions on the development of OA in subjects with OR
Compensation
• Definition of consensus criteria for grading impairment/ disability resulting from OR
Abbreviations
AR: Allergic Rhinitis; ARIA: Allergic Rhinitis and its Impact on Asthma; HMW: High molecular weight; LMW: Low molecular weight; NA: Not available; NO: Nitric oxide; NPT: Nasal provocation test; OA: Occupational asthma; OR: Occupational rhinitis; PNIF: Peak nasal inspiratory flow; RADS: Reactive airways dysfunction syndrome; RUDS: Reactive upper airways dysfunction syndrome; VAS: Visual analogue scale; WER: Work-exacerbated rhin-itis; WRNS: Work-related nose symptoms.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
Appendix 1
Methodology of nasal provocation tests
Precautions
NPT should always be carried out in specially equipped facilities, by trained personnel, and under close medical supervision. In most subjects, the tests can be performed on an outpatient basis, restricting hospitalization to sub-jects who have severe late reactions [119]. Contra-indica-tions to NPT include pregnancy, recent infectious rhinitis or sinonasal surgery, atrophic rhinitis, and severe asthma [116,117]. Medications known to interfere with nasal response should be withdrawn according to their duration of action [116,117]. The best time to perform a NPT is in the morning in order to limit the effects of daily-life stim-uli (fumes, cold air, spicy foods, and exercise). Baseline assessment of symptoms and nasal functions should be performed after adaptation to room temperature for 30 minutes.
It is essential to ensure that the nasal response is specific to the tested occupational agent by performing a control test [97]. These control or sham tests make it possible to detect irritant or non specific hyperresponsiveness. The control substance is selected according to the nature of the occupational agent suspected of causing OR, for instance, diluent for NPTs with aqueous allergen solutions, lactose powder for NPTs with agent in powder form (flour, drugs, persulphates, etc.), pine dust for NPTs with wood dusts. New causal agents have to be tested in control subjects in order to ascertain the specificity of the nasal response.
Methods of exposure to occupational agents
Exposure in the laboratory
Exposure may take place differently according to the nature of the agents;
a) Water soluble HMW agents can be administered as aqueous solutions of allergens. Purified and standardized allergenic extracts should be used for NPTs when such rea-gents are available. Alternatively, extracts may be freshly prepared into saline (phenolated) solutions [97,203]. In these settings, the level of skin reactivity to the extract can be used as a guide for determining the initial concentra-tion that will be delivered to the patient, which will be 10 times more diluted than the concentration eliciting a skin reaction. In case of negative skin test, the initial dose of allergen should be in the range of 1:10.000 to 1:5000 wt/ vol or 50 to 100 PNU [116,117,119]. Aqueous solutions can be delivered using metered dose devices (sprays) as recently reviewed [118] or by means of nebulizers gener-ating aerosols according to dosimeter or tidal breathing protocols. Challenges may regard only one or both nos-trils. The latter could avoid the influence of the nasal cycle when monitoring nasal patency [88]. Using allergen solu-tions offers the advantage of delivering quantified doses and being a reproducible technique. The limitation of this
method is that the delivered extract may not represent the native allergens due to purification and extraction proce-dures, which may potentially lead to falsely negative test. Other methods of exposure such as syringes, pipettes, paper discs, and cotton pads [117] should be discouraged because they do not reproduce natural exposure [118].
b) For all other agents, exposure can be produced in vari-ous ways, depending on the chemical properties and the physical state of the agent suspected of causing OR. The agent may be delivered as an aerosol, vapour, gas or dry particles by reproducing as much as possible the condi-tions of exposure occurring at the workplace. In some cases exposure may be obtained by asking subjects to reproduce their usual work under close supervision [204]. All these tests should be performed in specifically dedi-cated challenge rooms. Ideally, the concentration of the agent should be controlled and maintained below permis-sible threshold levels. The level of total and respirable dust and, in some cases (e.g. isocyanates), the concentra-tion of chemicals can be continuously monitored and modified during NPTs. The duration of challenge expo-sure should be gradually increased under close monitor-ing of nasal response. Subjects should be exposed for up to 2 hours before the test can be considered negative [204,205].
Workplace exposure
Workplace challenges may be considered when exposure to specific suspected agents is not possible, which may occur in the following settings: (1) no sensitizing agent has been firmly identified at work, (2) multiple poten-tially sensitizing agents are present at the workplace, or (3) the conditions of exposure at work cannot be repro-duced in the laboratory (e.g. complex industrial proc-esses) [206] 4) NPTs in the lab are not feasible for unavailability of equipped facilities. During these tests, the worker performs his or her usual tasks, and indices of nasal response are recorded before, during and after one (or several) work shift(s) with a time-schedule similar to that used during laboratory NPTs. Each patient should be compared to itself during a control day in order to ascer-tain sufficient reproducibility of outcome parameters. NPT at the workplace can also be a useful tool to investi-gate irritant-induced OR and work-exacerbated rhinitis [207,208].
Assessment of nasal response
[(i.e. compound symptom scores [120-122], visual ana-logue scales (VAS)] [199] nasal patency (i.e., using rhi-nomanometry, acoustic rhinometry and/or peak nasal inspiratory flow), and nasal inflammatory response (i.e., volume of nasal secretions, eosinophil counts and con-centrations of mediators in nasal secretions). Each of these methods has its own advantages and limitations, and their reproducibility has not been studied in large scale studies. There is general agreement that both subjec-tive and objecsubjec-tive indices must be considered, but unlike bronchial provocation tests, end-points for NPT are not standardized nor validated. Most frequently, the assess-ment of the response is made by measuring symptom score and changes in nasal patency [115,120]. There is, however, accumulating evidence that assessment of inflammatory cells (especially, eosinophils) and media-tors of inflammation (e.g. eosinophil cationic protein, tryptase) in nasal secretions could increase the specificity of NPTs with HMW [123,210-212] and LMW [213,214] agents and could be helpful for minimizing patient mis-classification. A recent study found that NPT with com-mon allergens induced a decrease in the level of nasal NO, which was followed by an increase at 7 and 24 hours post-challenge [215]. The role of nasal NO as a biomarker of airway inflammation during NPTs with occupational agents requires further investigation.
Pitfalls
A false-negative response on NPTs may occur if the wrong agent has been used, if the exposure conditions are not comparable with those encountered at the workplace, if the patient has been away from work for a long time [216] or if the patient is under nasal steroid treatment.
The most frequent reason for false-positive results in the measurements of nasal patency during NPTs is the effects of the nasal cycle. Other potential causes of false-positive results include a general hyperreactivity of nasal mucosa resulting from preceding exposure to allergens or irritants and episodes of rhinosinusitis ('nasal priming') [118,217-219].
Additional material
Acknowledgements
All the Authors are members of the EAACI Task Force On Occupational Rhinitis coordinated by Dr. Gianna Moscato.
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Additional file 1
Table 3. Compensation for occupational rhinitis in different countries. Click here for file
